Role In Venous Thromboembolism Research Articles

Association between lactate metabolism‑related molecules and venous thromboembolism: A study based on bioinformatics and an invitro model.

Venous thromboembolism (VTE) is characterized by a high recurrence rate and adverse consequences, including high mortality. Damage to vascular endothelial cells (VECs) serves a key role in VTE and lactate (LA) metabolism is associated with VEC damage. However, the pathogenesis of VTE and the role of lactate metabolism-related molecules (LMRMs) remain unclear. Based on the GSE48000 dataset, the present study identified differentially expressed (DE-)LMRMs between healthy individuals and those with VTE. Thereafter, LMRMs were used to establish four machine learning models, namely, the random forest, support vector machine and generalized linear model (GLM) and eXtreme gradient boosting. To verify disease prediction efficiency of the models, nomograms, calibration curves, decision curve analyses and external datasets were used. The optimal machine learning model was used to predict genes involved in disease and an in vitro oxygen-glucose deprivation (OGD) model was used to detect the survival rate, LA levels and LMRM expression levels of VECs. A total of four DE-LMRMs, solute carrier family 16 member 1 (SLC16A1), SLC16A7, SLC16A8 and SLC5A12 were obtained and GLM was identified as the best performing model based on its ability to predict differential expression of the embigin, lactate dehydrogenase B, SLC16A1, SLC5A12 and SLC16A8 genes. Additionally, SLC16A1, SLC16A7 and SLC16A8 served key roles in VTE and the OGD model demonstrated a significant decrease in VEC survival rate as well as a significant increase and decrease in intracellular LA and SLC16A1 expression levels in VECs, respectively. Thus, LMRMs may be involved in VTE pathogenesis and be used to build accurate VTE prediction models. Further, it was hypothesized that the observed increase in intracellular LA levels in VECS was associated with the decrease in SLC16A1 expression. Therefore, SLC16A1 expression may be an essential target for VTE treatment.

A Mouse Model of the PAR4 Sequence Variant P310L Shows Decreased Platelet Reactivity and Thrombosis

Protease activated receptors 1 and 4 (PAR1, PAR4) on platelets mediate thrombin signaling and are vital for thrombus development. Hypercoagulation and thrombin generation are major risk factors for thrombosis. Sustained thrombin signaling through PAR4 promotes platelet activation, phosphatidylserine exposure, and subsequent thrombin generation. A single-nucleotide polymorphism (SNP, rs2227376) leads to an amino acid change in extracellular loop 3 (ECL3) of PAR4, which decreases PAR4 activation (PAR4-P310L). This SNP is also associated with a significantly lower risk for venous thromboembolism (VTE) in a GWAS meta-analysis. We aim to determine the mechanism by which PAR4-P310L (rs2227376) impacts platelet function and reduces the risk of VTE using mice with a homologous mutation (PAR4-P322L). Ex vivo platelet function was determined using flow cytometry and aggregometry. Arterial and venous thrombosis was examined using the ferric-chloride induced carotid artery injury and inferior vena cava (IVC) stasis models, respectively. Platelets from heterozygous (PAR4-322P/L) and homozygous (PAR4-322L/L) mice had decreased thrombin-mediated aggregation and decreased PAR4 reactivity compared to wild types. These mice also had a prolonged time to occlusion in arterial thrombosis, with 55% of PAR4-322P/L mice unable to develop stable thrombi within 30 minutes. In venous thrombosis, wild-type mice developed clotted IVCs that averaged 31 mg after 48 hours, while global PAR4-knockout mice averaged 21 mg (p<0.01), PAR4-322P/L 23 mg (p<0.01), and PAR4-322L/L 28 mg. Since platelet procoagulant activity is known to drive venous thrombosis, we used lactadherin to show that PAR4-P322L platelets express less phosphatidylserine in response to thrombin (5 nM) and convulxin (1 nM). Platelet-rich plasma from PAR4-P322L mice also generated less thrombin compared to wild-types, and whole blood from mice lacking PAR4 showed delayed clot formation in rotational thromboelastometry. Altogether, this suggests a direct impact of PAR4 signaling on platelet-mediated thrombin generation. Our new mouse model shows that the polymorphism in ECL3, PAR4-322L, decreases platelet reactivity and thrombosis. We also show PAR4-322L leads to less procoagulant platelets and decreases the endogenous thrombin potential. This decreased ability to generate thrombin offers a mechanism for PAR4's role in VTE. Our findings highlight a key role of PAR4 signaling in platelet activation and procoagulant activity in thrombosis.

Acute Myocardial Infarction in Patients with Hereditary Thrombophilia-A Focus on Factor V Leiden and Prothrombin G20210A.

Factor V (FV) Leiden and prothrombin G20210A are the most common hereditary thrombophilias. While their role in venous thromboembolism is well known, there are still uncertainties regarding their relationship with arterial thrombotic events, especially coronary ones. Our research, based on an in-depth analysis of the available literature, provides up-to-date information on the relationship between FV Leiden and prothrombin G20210A and acute myocardial infarction. FV Leiden and prothrombin G20210A screening should be implemented only in select cases, such as acute coronary syndrome in young individuals and/or in the absence of traditional cardiovascular risk factors and/or in the absence of significant coronary artery stenosis at angiography. Their identification should be followed by the implementation of optimal control of modifiable traditional cardiovascular risk factors to reduce the risk of recurrent events and genotyping and genetic counseling of all family members of affected cases for proper prophylaxis. An extended dual antiplatelet therapy (DAPT) may be considered, given the lower risk of bleeding under DAPT conferred by FV Leiden.

Heightened Procoagulation after Post-Operative Thromboprophylaxis Completion in Patients with Metastatic Bone Disease from Primary Colorectal Cancer.

Platelets play a role in venous thromboembolism (VTE) and in mediating colorectal cancer (CRC) progression. Still, platelets' role in hypercoagulability after surgical intervention for metastatic bone disease (MBD) is ill-defined. In this quantitative observational study, we utilized a high-resolution imaging approach to temporally examine platelet procoagulant membrane dynamics (PMD) in four patients with MBD from primary CRC (CRC/MBD), before and after surgical intervention, over a 6-month period. We coupled this investigation with thrombelastography, quantitative plasma shotgun proteomics, and biochemical analysis. The plasma of CRC/MBD patients was enriched in ADAM1a, ADAMTS7, and physiological ligands for platelet glycoprotein-VI/spleen tyrosine kinase (GPVI/Syk) activation. Thromboprophylaxis attenuated procoagulation upon its initial prescription (post-operative day one, POD1); however, all patients experienced rebound procoagulation between POD3 and POD14, which was associated with Syk activation (Y525/Y526) in all patients, and a VTE event in two patients. Plasma levels of DNA-histone complexes increased steadily after surgery and remained elevated throughout the study period. Additionally, we increasingly sighted both homotypic and heterotypic platelet microaggregates after surgery in CRC/MBD patients, but not in healthy control participants' plasma. Our data elucidates the cell biology of a prothrombo-inflammatory state caused by disease and vascular injury, and recalcitrant to thromboprophylaxis. New mechanistic insights into hypercoagulability in CRC/MBD patients may identify novel drug targets for effective thromboprophylaxis type and duration after orthopaedic surgery.

Small RNA Sequencing Reveals Exosomal miRNAs as Unique Feature Markers in Unprovoked Venous Thromboembolism

Introduction: Venous thromboembolism (VTE) is a common cardiovascular disease. MicroRNAs (miRNAs) play a key role in VTE; however, the role of exosomal miRNAs in VTE remains unknown. Therefore, we aimed to identify key exosomal miRNAs and their potential mechanisms in VTE. Methods: We collected 31 samples from unprovoked VTE patients and 25 samples from healthy individuals. Exosomal miRNA sequencing was performed on 11 unprovoked VTE samples and 9 normal samples, and the remaining samples were used to verify the expression level of candidate 9 miRNAs in VTE and normal samples. The sequencing data were used to analyze exosomal miRNA expression. Meanwhile, gene ontology and Kyoto Encyclopedia of Genes and Genomes analyses were performed to determine the potential biological functions of differentially expressed miRNA target genes. Results: A total of 32 differentially expressed miRNAs were identified by sequencing. Among the 32 miRNAs, 23 miRNAs were upregulated (72%), and 9 miRNAs were downregulated (28%). In addition, we found that the biological functions and metabolic pathways of the target genes were related to hemostatic factors involved in VTE, indicating the regulation of differentially expressed miRNAs. We identified key miRNAs by constructing a miRNA-messenger RNA regulatory network and found that the target genes were related to VTE. We finally determined that the abnormal expression of 9 miRNAs is closely related to VTE, and the expression level between VTE and normal was verified through other samples. Conclusion: Our study identified a set of key miRNAs for future research on the molecular mechanisms of VTE.

Meta-analysis of alcohol consumption and venous thromboembolism.

The associations of alcohol consumption and venous thromboembolism (VTE) have been investigated widely, but the conclusions were inconsistent. To summarize the relationship of alcohol consumption and VTE. This study has been registered in PROSPERO (ID: CRD42020164567). We searched the PubMed, Embase, Web of Science and the Cochrane Library databases from inception to September 2019 and reviewed the reference list of relevant articles to identify studies assessing the association between alcohol consumption and risk of VTE. Fourteen cohorts and four case-control studies were included in the meta-analysis. Compared with non-drinkers, the risk of VTE was decreased (RR: 0.93; 95% confidence interval [CI] 0.88-0.99) for alcohol drinkers. The pooled RRs of VTE were 0.91 (95% CI 0.84-0.99) for low to moderate alcohol intake (0.1-14.0 drinks/week) and 0.91 (95% CI 0.78-1.06) for high alcohol intake (>14.0 drinks/week) compared with non-drinker. Subgroup analysis showed liquor intake might slightly increase the risk of VTE (1.01; 95% CI 0.85-1.21) although the difference was not significant. Alcohol consumption in low to moderate was associated with a lower risk of VTE. However, precautions are needed when providing personal drinking advice considering the potential harm of alcohol. Further studies are warranted to determine whether moderate alcohol consumption has a causal role in VTE.

Bioinformatics Analysis and Identification of Genes and Molecular Pathways Involved in Venous Thromboembolism (VTE)

ObjectivesTo explore the key genes, and correlated pathways in venous thromboembolism (VTE) via bioinformatic analysis, and expected our findings could contribute to the development of new biomarkers and therapeutic target for VTE. MethodsTwo VTE‐related microarray expression profiles (GSE48000 and GSE19151) were downloaded from the Gene Expression Ominibus (GEO) database. Differentially expressed genes (DEGs) were analyzed using limma package, and overlapping DEGs were identified form the above two expression profiles. Then, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEEG) pathway enrichment analyses were performed by DAVID. Protein-protein interaction (PPI) network was constructed by using STRING and visualized with Cytoscape. Furthermore, module analysis plus centrality analysis of the PPI network were executed to identify the potential key genes. Finally, the pathway analysis was performed using GenCLiP 3.0. ResultsA total of 173 DEGs (125 upregulated and 48 downregulated) were identified. GO analysis demonstrated that DEGs were mainly enriched in viral life cycle, ribosome and structural constituent of ribosome. Meanwhile, KEGG pathway analysis showed that these genes were enriched in ribosome, Parkinson's disease and cell cycle. Additionally, one most significant module and 12 hub genes were found. Finally, 6 key genes, namely ISG15, RPS15A, MRPL13, ICT1, MRPL15 and RPLP0, with high centrality features were identified. These key genes were mainly involved in translation, metabolism of proteins and ribosome pathway. ConclusionsIn summary, these 6 identified genes and correlated pathways should play an important role in VTE, which can provide new insight into the molecular mechanism, potential biomarkers and therapeutic targets associated with VTE.

Inter-Relationship between Platelet-Derived Microparticles and Oxidative Stress in Patients with Venous Thromboembolism.

Background: Hypercoagulative conditions play a key role in venous thromboembolism (VTE). Inflammation is currently linked to VTE, but the potential role of circulating microparticles and oxidative stress (OxS) must be elucidated. The aim of this study was to evaluate platelet-derived microparticles and surrogate OxS biomarkers in patients diagnosed with VTE through a case–control study. Methods: Platelet-derived microparticles (MPs), pro-thrombinase-induced clotting time assay (PiCT), phospholipids (PLPs), malondialdehyde (MDA), 4-hydroxynonenale (4-HNE), thiobarbituric acid reactive substances (TBARs), superoxide dismutase (SOD), and galectin-3 (Gal-3) were measured in VTE patients and in healthy controls. Results: PLPs, 4-HNE, TBARs, and Gal-3 were higher in VTE patients compared to controls; conversely, SOD was lower. A significant non-linear regression between OxS biomarkers and the markers of platelet degranulation was found. Conclusion: Our results suggest that OxS and platelet degranulation are concomitant pathophysiological mechanisms in VTE.

Influence of Tobacco Smoking on Perioperative Risk of Venous Thromboembolism.

Venous thromboembolism (VTE) is generally considered a process very different from arterial atherosclerosis. The role of tobacco is well known in arterial thrombosis. However, its role in VTE is less obvious and remains controversial. In this mini review, we analysed the literature to identify the role of active or passive smoking in perioperative VTE and the relationship between arterial atherosclerosis and VTE. We carried an Internet search in French and English including the following keywords: deep vein thrombosis, tobacco, cigarette smoking, pulmonary embolism, postoperative, postoperative, atherosclerosis. Regarding the relationship between tobacco and VTE, a total of 9 studies were identified. Studies were ranked by the risk of VTE in relation to active or passive smoking. In conclusion, the management of smoking during the perioperative period for a short-term arrest (minimum 4–8 weeks before the intervention), or long term, allows among others a reduction of arterial or venous thrombotic events. However, it is clear that the training of anaesthesiologists in the management of smoking will contribute to the reduction of this public health problem.

Predicting venous thromboembolism risk from exomes in the Critical Assessment of Genome Interpretation (CAGI) challenges.

Genetics play a key role in venous thromboembolism (VTE) risk, however established risk factors in European populations do not translate to individuals of African descent because of the differences in allele frequencies between populations. As part of the fifth iteration of the Critical Assessment of Genome Interpretation, participants were asked to predict VTE status in exome data from African American subjects. Participants were provided with 103 unlabeled exomes from patients treated with warfarin for non-VTE causes or VTE and asked to predict which disease each subject had been treated for. Given the lack of training data, many participants opted to use unsupervised machine learning methods, clustering the exomes by variation in genes known to be associated with VTE. The best performing method using only VTE related genes achieved an area under the ROC curve of 0.65. Here, we discuss the range of methods used in the prediction of VTE from sequence data and explore some of the difficulties of conducting a challenge with known confounders. In addition, we show that an existing genetic risk score for VTE that was developed in European subjects works well in African Americans.

Searching for a Common Thrombo-Inflammatory Basis in Patients With Deep Vein Thrombosis or Peripheral Artery Disease.

Background: Inflammation and hypercoagulability play a pivotal role in venous thromboembolism and atherothrombosis. Since venous thrombosis increases the risk of atherothrombotic events and vice versa, common mechanisms may be involved.Objectives: To elucidate the role of neutrophils and coagulation in the occurrence of atherothrombotic events in patients with a history of deep vein thrombosis (DVT or peripheral artery disease (PAD).Materials and Methods: We studied 115 patients from two cohorts (75 DVT, 40 PAD). From those with PAD, 20 patients had progressive disease; from those with DVT, 25 patients had a recurrent DVT and 25 suffered from post thrombotic syndrome (PTS); patients were age and sex matched to DVT and PAD patients without events. Markers of neutrophil recruitment (p-selectin) and activation [nucleosomes, human neutrophil elastase- α1anti-trypsin (HNE-AT)], an anti-inflammatory marker (Lipoxin A4) and a clotting activity marker (d-dimer), were measured with ELISA. Coagulation potential was analyzed by thrombin generation (CAT method).Results: Higher nucleosome levels were found in DVT patients [11.3 U/mL (7.4–17.7)] compared to PAD patients [7.1 U/mL (5.1–13.8)], lower HNE-AT levels were found in DVT patients [33.4 ng/mL (23.5–40.5)] in comparison to PAD patients [158 ng/mL (88.1–283)]. No difference in nucleosome levels was found between DVT patients with cardiovascular (CV) events [12.6 U/mL (8.2–16.1)], and PAD patients with CV events [6.9 U/mL (4.9–11.2)]. Lipoxin A4 levels appeared to be significantly lower in DVT [2.4 ng/mL (1.7–4.8)] vs. PAD [35.6 ng/mL (16.6–80.1)], with similar results in DVT patients with CV events vs. PAD patients with CV events. Thrombin generation showed higher ETP [160.4% (141.1–215.4)], and peak height [292.1% (177.9–330)] values in DVT patients. D-dimer levels were significantly lower in the DVT cohort [330 ng/mL (220–550)] compared to the PAD cohort [550 ng/mL (369–959)].Conclusion: In DVT patients, neutrophil activity does not appear to be an important driver of CV events. Although neutrophil activity is more pronounced in PAD, its effect is partly dampened by Lipoxin A4. Moreover, no associations were found between NET products and coagulation activity, suggesting that neutrophil activation does not play a pivotal role in the risk of thrombosis in either DVT or PAD.

Recurrent venous thromboembolism patients form clots with lower elastic modulus than those formed by patients with non‐recurrent disease

Essentials Venous thromboembolism (VTE) recurrence leads to decreased clot elastic modulus in plasma.Recurrent VTE is not linked to changes in clot structure, fiber radius, or factor XIII activity.Other plasma components may play a role in VTE recurrence.Prospective studies should resolve if clot stiffness can be used as predictor for recurrent VTE. SummaryBackgroundVenous thromboembolism (VTE) is associated with a high risk of recurrent events after withdrawal of anticoagulation.ObjectivesTo determine the difference in plasma clot mechanical properties between patients with recurrent VTE (rVTE) and those with non‐recurrent VTE (nrVTE).MethodsWe previously developed a system for determining clot mechanical properties by use of an in‐house magnetic tweezers system. This system was used to determine the mechanical properties of clots made from plasma of 11 patients with rVTE and 33 with nrVTE. Plasma was mixed with micrometer‐sized beads, and thrombin and calcium were added to induce clotting; the mixture was then placed in small capillary tubes, and clotting was allowed to proceed overnight. Bead displacements upon manipulation with magnetic forces were analyzed to determine clot elastic and viscous moduli. Fibrin clot structure was analyzed with turbidimetry and confocal microscopy. Factor XIII was measured by pentylamine incorporation into fibrin.ResultsClots from rVTE patients showed nearly two‐fold less elastic and less viscous moduli than clots from nrVTE patients, regardless of male sex, unprovoked events, family history of VTE, fibrinogen concentration, or body mass index. No differences were observed in clot structure, fibrinolysis rates, or FXIII levels.ConclusionUsing magnetic tweezers for the first time in patient samples, we found that plasma clots from rVTE patients showed a reduced elastic modulus and a reduced viscous modulus as compared with clots from nrVTE patients. These data indicate a possible role for fibrin clot viscoelastic properties in determining VTE recurrence.

Plasma Concentrations of High Molecular Weight Kininogen and Prekallikrein and Venous Thromboembolism Incidence in the General Population.

The kallikrein/kinin system, an intravascular biochemical pathway that includes several proteins involved in the contact activation system of coagulation, renin-angiotensin activation and inflammation, may or may not play a role in venous thromboembolism (VTE) occurrence. Within a large prospective population-based study in the United States, we conducted a nested case-cohort study to test the hypothesis that higher plasma levels of high molecular weight kininogen (HK) or prekallikrein are associated with greater VTE incidence. We related baseline enzyme-linked immunosorbent assay measures of HK and prekallikrein in 1993 to 1995 to incidence VTE of the lower extremity (n = 612) through 2015 (mean follow-up = 18 years). We found no evidence that plasma HK or prekallikrein was associated positively with incident VTE. HK, in fact, was associated inversely and significantly with VTE in most proportional hazards regression models. For example, the hazard ratio of VTE per standard deviation higher HK concentration was 0.88 (95% confidence interval = 0.81, 0.97), after adjustment for several VTE risk factors. Our findings suggest that plasma levels of these factors do not determine the risk of VTE in the general population.

Platelet to Lymphocyte Ratio and Neutrophil to Lymphocyte Ratio as Risk Factors for Venous Thrombosis.

High platelet to lymphocyte ratio (PLR) and neutrophil to lymphocyte ratio (NLR) are associated with an increased risk of arterial thrombosis, but their role in venous thromboembolism (VTE) has not been fully investigated. A case–control study, of 486 patients with VTE, 100 with cerebral vein thrombosis (CVT), and 299 healthy individuals, was carried out to investigate whether high PLR or NLR values are associated with an increased risk of VTE. Patients with high PLR or NLR did not have an increased risk of VTE (odds ratio [OR] 0.89, 95% confidence interval [CI]: 0.46-1.76; OR: 0.69, 95% CI: 0.34-1.39, respectively) or CVT (OR: 1.65, 95% CI: 0.68-4.00; OR: 0.39, 95% CI: 0.09-1.72, respectively). Subgroups analysis showed that high PLR values were associated with the risk of provoked CVT (OR: 2.65, 95% CI: 1.02-6.92), and there was an interaction with thrombophilia abnormalities (OR: 7.67, 95% CI: 1.67-35.27) in patients with CVT. In conclusion, high PLR and NLR values are not associated with an overall increased risk of VTE or CVT. High PLR values increase the risk of provoked CVT and interact with thrombophilia abnormalities in patients with CVT.

Procoagulant activity of extracellular vesicles as a potential biomarker for risk of thrombosis and DIC in patients with acute leukaemia.

Haemostatic complication is common for patients with hematologic malignancies. Recent studies suggest that the procoagulant activity (PCA) of extracellular vesicles (EV) may play a major role in venous thromboembolism and disseminated intravascular coagulation (DIC) in acute leukaemia. To study the impact of EVs from leukaemic patients on thrombin generation and to assess EV-PCA as a potential biomarker for thrombotic complications in patients with acute leukaemia. Blood samples from a cohort of patients with newly diagnosed acute leukaemia were obtained before treatment (D-0), 3 and 7days after treatment (D-3 and D-7). Extracellular vesicles were isolated and concentrated by ultracentrifugation. EV-PCA was assessed by thrombin generation assay, and EV-associated tissue factor activity was measured using a commercial bio-immunoassay (Zymuphen MP-TF®). Of the 53 patients, 6 had increased EV-PCA at D-0 and 4 had a thrombotic event. Patients without thrombotic events (n = 47) had no elevated EV-PCA. One patient had increased EVs with procoagulant activity at D-3 and developed a DIC at D-5. This patient had no increased EVs-related tissue factor activity from D-0 to D-7 (<2pg/ml). Eight patients had increased EVs with tissue factor activity (>2pg/ml), of these, four had a thrombosis and two had haemorrhages. Procoagulant activity of extracellular vesicles could have a predictive value in excluding the risk of thrombotic events. Our findings also suggest a possible association between thrombotic events and EV-PCA.

Platelet Function in Thrombosis and Hemostasis.

Platelets represent the main effectors in the formation of the initial hemostatic plug through an elaborate response to vascular injury, and furthermore, platelets play an essential role in secondary hemostasis.1 However, platelets are also important contributors to pathological thrombus formation and vessel occlusion when activated inappropriately. Moreover, platelets contribute to processes beyond hemostasis and thrombosis such as inflammation, wound healing, and maintenance of vascular integrity.2 In the present issue of Seminars inThrombosis &Hemostasis, the focus is on the physiology of platelets as well as diagnostic issues, both as regard to bleeding disorders and thromboembolic risk. In a series of articles, the issue provides an overviewof some of themain conditions influencing platelet function and of different diagnostic approaches to investigating platelet function. The role of platelets in cardiovascular disease and venous thromboembolism and the effect of antiplatelet drugs are reviewed and discussed in another series of articles. First, Lassila introduces the reader to the overall role of platelets as well as issues to consider when testing platelet function in bleeding disorders.3 Following this introduction, Gremmel et al provide a comprehensive review on platelet physiology, with particular focus on structure, granules, surface glycoproteins, and activation pathways.4 The authors illustrate how new imaging techniques have improved the knowledge on platelet structure, secretion, adhesion, and activation, and how these techniques have expanded our understanding of the role of platelets in health and disease. Recent research has revealed platelets as more active components of the immune system besides the previously considered passive immune-modulatory role. Through a cross-talk with the immune system, platelets have emerged as both critical modulators of atherothrombosis and vascular inflammation and as effector cells in the combat of microbial infection. Chatterjee and Geisler provide an overview of the complex area of platelet-derived targets involved in inflammatory pathways and platelets as regulator of the immune system.5 Although platelets are anucleate cells, they retain many of the RNA metabolic processes of nucleated cells. Lindsay and Edelstein outline the current knowledge as regard to platelets and microRNA, and the possible role for platelet function in disease and in the regulation of platelet physiology.6 The subsequent section contains reviews on the role of platelets in several disease entities. First, Pasalic et al discuss biomarkers of cardiovascular disease with focus on the role of platelets.7 They also provide a comprehensive review presenting the significance of measures of platelet activity and platelet aggregation as risk markers of cardiovascular disease. Several methods of platelet function testing have been evaluated for these conditions, but these data remain conflicting, and platelet biomarkers have not beenwidely incorporated in cardiovascular risk scores so far. The risk of cardiovascular disease among patients with type 2 diabetes mellitus has attracted increased attention during the recent decades. The significance is underlined by the fact that patients with prediabetes also have an increased risk of cardiovascular events.8 Therefore, Neergaard-Petersen et al summarize current knowledge on the potential cardiovascular role of platelets in patients with diabetes.9 This review also provides an updated status on the benefits and limitations of antiplatelet therapy in diabetic patients with cardiovascular disease. As regard to thromboembolic disease, platelets have been ascribed far more significance in arterial cardiovascular disease than in venous thromboembolic disease. MontoroGarcia et al present recent evidence suggesting that platelets may play a more important role in venous thromboembolism than previously anticipated.10 This review also discusses the potential applications of platelets as novel risk factors for venous thromboembolic disease. The authors additionally point to future important issues, such as whether the contribution of platelet-associated risk factors is dependent on

The Role of Platelets in Venous Thromboembolism.

Multiple factors contribute to the risk of venous thromboembolism (VTE). Platelets have attracted much interest in arterial cardiovascular disease, whereas their role in VTE has received much less attention. Recent evidence suggests that platelets may play a more important role in VTE than previously anticipated. This review discusses the mechanisms that link platelets with venous thrombotic disease and their potential applications as novel risk factors for VTE. In addition, animal studies and randomized clinical trials that highlight the potential effect of antiplatelet therapy in venous thrombosis are evaluated to assess the role of platelets in VTE. The clinical significance of platelets for VTE risk assessment in specific patient cohorts and their role as a suitable therapeutic target for VTE prevention is acknowledged. The role of platelets in VTE is a promising field for future research.

Genetic Risk Factors in Venous Thromboembolism.

Genetic risk factors predispose to thrombophilia and play the most important etiopathogenic role in venous thromboembolism (VTE) in people younger than 50years old. At least one inherited risk factor could be found in about half of the cases with a first episode of idiopathic VTE.Roughly, genetic risk factors are classified into two main categories: loss of function mutations (such as deficiencies of antithrombin, protein C, protein S) and gain of function mutations, (such as prothrombin mutation G20210A, factor V Leiden). A revolutionary contribution to the genetic background of VTE was brought by the achievements of the genome-wide association studies which analyze the association of a huge number of polymorphisms in large sample size.Hereditary thrombophilia testing should be done only in selected cases. The detection of hereditary thrombophilia has impact on the management of the anticoagulation in children with purpura fulminans, pregnant women at risk of VTE and may be useful in the assessment of the risk for recurrent thrombosis in patients presenting an episode of VTE at a young age (<40years) and in cases with positive family history regarding thrombosis.

Understanding Genetic Variations as Risk Factors for Development Venous Thrombo-Embolism (VTE)

Venous thrombosis (VT) possess a major health problem worldwide and has a high incidence in several populations across the world. Its two clinical manifestations include deep vein thrombosis (DVT) and pulmonary embolism (PE). The pathogenetic mechanism of venous thromboembolism (VTE) is still not completely elucidated, however there are clear evidences that the process occurs by complex interaction of genetic and environmental factors, wherein, genetic risk factors plays a major role. These numerous conditions that are known for predisposition of venous thromboembolism are commonly referred to as ‘risk factors’. Classical risk factors for VTE include advancing age, prolonged immobilization, surgery, use of oral contraceptives or hormones, pregnancy, cancer etc. However, in the recent decades, studies have emerged that indicating a major role of novel genetic risk factors. These genetic risk factors include genes related to haemostatic system and coagulation cascade. Understanding the of role of these genes as predisposing factors for VTE represent a crucial step for a better understanding of pathogenesis of thrombosis. Several genes that have been studied for their mutations playing a role in VTE are factor V Leiden (FVL), antithrombin (AT), protein C, protein S, prothrombin, fibrinogen etc. The risk associated with each genetic defect might be relatively insignificant when studied individually but simultaneous involvement of several mutations increase the risk of susceptibility. In addition to this, acquired risk factors interacting with one or more genetic variations further add to the risk of VTE. This review has been complied to interrogate the role of several genetic and acquired risk factors across various populations as investigated in numerous studies.

Bevacizumab promotes venous thromboembolism through the induction of PAI-1 in a mouse xenograft model of human lung carcinoma.

BackgroundAn increased incidence of venous thromboembolism (VTE) is associated with anti-vascular endothelial growth factor (VEGF) treatment in cancer. However, the mechanism underlying this effect remains elusive. In this study, we examined the effect of bevacizumab, a humanized monoclonal antibody against VEGF-A, on VTE in a murine xenograft A549 cell tumor model.MethodsInferior vena cava stenosis model and FeCl3-induced saphenous vein thrombosis model were performed in a mouse xenograft models of human lung adenocarcinoma.ResultsWe found that treatment with bevacizumab significantly increased the thrombotic response to inferior vena cava obstruction and femoral vein injury. Plasminogen activator inhibitor (PAI-1) expression in tumors, plasma, and thrombi was significantly increased by bevacizumab. However, bevacizumab did not enhance VTE in PAI-1-deficient mice, suggesting that PAI-1 is a major mediator of bevacizumab’s prothrombotic effect. VEGF inhibited expression of PAI-1 by A549 cells, and this effect was neutralized by bevacizumab, suggesting that bevacizumab increases PAI-1 expression in vivo by blocking the inhibitory effect of VEGF on PAI-1 expression by tumor cells. Pharmacological inhibition of PAI-1 with PAI-039 blocked bevacizumab-induced venous thrombosis.ConclusionCollectively, these findings indicate that PAI-1 plays a role in VTE associated with antiangiogenic therapy and the inhibition of PAI-1 shows efficacy as a therapeutic strategy for the prevention of bevacizumab-associated VTE.